title: Weekly nab-Rapamycin in patients with advanced nonhematologic malignancies: final results of a phase I trial.
abstract: OBJECTIVE
  This dose-finding phase I study investigated the maximum-tolerated dose (MTD) and safety of weekly nanoparticle albumin-bound rapamycin (nab-rapamycin) in patients with untreatable advanced nonhematologic malignancies.
  
  
  METHODS
  nab-Rapamycin was administered weekly for 3 weeks followed by 1 week of rest, with a starting dose of 45 mg/m(2). Additional doses were 56.25, 100, 150, and 125 mg/m(2).
  
  
  RESULTS
  Of 27 enrolled patients, 26 were treated. Two dose-limiting toxicities (DLT) occurred at 150 mg/m(2) [grade 3 aspartate aminotransferase (AST) elevation and grade 4 thrombocytopenia], and two DLTs occurred at 125 mg/m(2) (grade 3 suicidal ideation and grade 3 hypophosphatemia). Thus, the MTD was declared at 100 mg/m(2). Most treatment-related adverse events (TRAE) were grade 1/2, including thrombocytopenia (58%), hypokalemia (23%), mucositis (38%), fatigue (27%), rash (23%), diarrhea (23%), nausea (19%), anemia (19%), hypophosphatemia (19%), neutropenia (15%), and hypertriglyceridemia (15%). Only one grade 3 nonhematologic TRAE (dyspnea) and one grade 3 hematologic event (anemia) occurred at the MTD. One patient with kidney cancer had a partial response and 2 patients remained on study for 365 days (patient with mesothelioma) and 238 days (patient with neuroendocrine tumor). The peak concentration (Cmax) and area under the concentration-time curve (AUC) of rapamycin increased with dose between 45 and 150 mg/m(2), except for a relatively low AUC at 125 mg/m(2). nab-Rapamycin significantly inhibited mTOR targets S6K and 4EBP1.
  
  
  CONCLUSIONS
  The clinical dose of single-agent nab-rapamycin was established at 100 mg/m(2) weekly (3 of 4 weeks) given intravenously, which was well tolerated with preliminary evidence of response and stable disease, and produced a fairly dose-proportional pharmacokinetic profile in patients with unresectable advanced nonhematologic malignancies.
authors.affiliation: Authors' Affiliations: Departments of Breast Medical Oncology and Systems Biology, Surgical Oncology, and Investigational Cancer Therapeutics, The University of Texas MD Anderson Cancer Center, Houston, Texas; Sarcoma Oncology Center, Santa Monica; Division of Hematology-Oncology, University of California, San Diego, California; and Celgene, Summit, New Jersey.
authors.forename: Ana M
authors.initials: AM
authors.lastname: Gonzalez-Angulo
authors.forename: Funda
authors.initials: F
authors.lastname: Meric-Bernstam
authors.forename: Sant
authors.initials: S
authors.lastname: Chawla
authors.forename: Gerald
authors.initials: G
authors.lastname: Falchook
authors.forename: David
authors.initials: D
authors.lastname: Hong
authors.forename: Argun
authors.initials: A
authors.lastname: Akcakanat
authors.forename: Huiqin
authors.initials: H
authors.lastname: Chen
authors.forename: Aung
authors.initials: A
authors.lastname: Naing
authors.forename: Siqing
authors.initials: S
authors.lastname: Fu
authors.forename: Jennifer
authors.initials: J
authors.lastname: Wheler
authors.forename: Stacy
authors.initials: S
authors.lastname: Moulder
authors.forename: Thorunn
authors.initials: T
authors.lastname: Helgason
authors.forename: Shaoyi
authors.initials: S
authors.lastname: Li
authors.forename: Ileana
authors.initials: I
authors.lastname: Elias
authors.forename: Neil
authors.initials: N
authors.lastname: Desai
authors.forename: Razelle
authors.initials: R
authors.lastname: Kurzrock
mesh_terms: D000293:Adolescent; D000328:Adult; D000368:Aged; D000903:Antibiotics, Antineoplastic / Q000494:pharmacology / Q000627:therapeutic use*; D004334:Drug Administration Schedule; D005260:Female; D006801:Humans; D008297:Male; D020714:Maximum Tolerated Dose; D008875:Middle Aged; D009367:Neoplasm Staging; D009369:Neoplasms / Q000175:diagnosis* / Q000188:drug therapy*; D020123:Sirolimus / Q000494:pharmacology / Q000627:therapeutic use*; D016896:Treatment Outcome; D055815:Young Adult
chemical_list: D000903:Antibiotics, Antineoplastic; D020123:Sirolimus